This project sets out to advance the field of nucleic acid therapeutics, which is likely to have a transformative effect on the treatment and prevention of human disease through the altered expression of problematic gene targets. Specifically, this study will attempt to address the challenges associated with the non-toxic delivery of DNA and siRNA through the investigation of lipid-like delivery vehicles (which we term 'lipidoids'). The general objectives of this proposal include: 1. Development of high-quality candidates for the safe and effective delivery of nucleic acids using lipidoid delivery nanoparticles. 2. Exploration of the underlying mechanisms of lipidoid-based delivery in order to enable the insightful design of future generations of lipidoid delivery agents. These general objectives will be accomplished first through the high throughput chemical synthesis of a large library of new and diverse lipidoid nanoparticles. These lipidoids will be screened for their ability to deliver nucleic acids to HeLa cells in a non-toxic fashion. Leading candidates will be further examined for therapeutic potential in animals. Finally, in order to enable the improved design of future libraries of lipidoid delivery vehicles, we will attempt to gain insight into lipidoid delivery mechanisms. This will be accomplished through transport studies using fluorescent particle tracking as well as molecular modeling studies intended to identify structure-function relationships for lipidoids. We expect that such experiments will lead to exciting new materials capable of specific gene manipulation as well as a better understanding of lipidoid function. Nucleic acid therapeutics has the potential to revolutionize the field of disease treatment and prevention once the challenges associated with delivery are overcome. This study will investigate the ability of nanoparticles made from lipid-like materials to safely and effectively deliver siRNA and DNA while gaining insight into the mechanisms of delivery action.